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© 2020 European Society of Endocrinology
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https://doi.org/10.1530/EJE-19-0893
European Journal of Endocrinology
182:1 G1–G32
R Pasquali and others ESE Guidelines on Endocrine work-up in obesity
European Society of Endocrinology Clinical
Practice Guideline: Endocrine work-up in
obesity
R Pasquali1, F Casanueva2, M Haluzik3, L van Hulsteijn4, S Ledoux5, M P Monteiro6,7, J Salvador8,9, F Santini10,
H Toplak11 and O M Dekkers12,13,14
1University Alma Mater Studiorum, Bologna, Italy, 2Department of Medicine, Santiago de Compostela University, Complejo Hospitalario
Universitario de Santiago (CHUS), CIBER de Fisiopatologia Obesidad y Nutricion (CIBERobn), Instituto Salud Carlos III, Santiago de
Compostela, Spain, 3Diabetes Centre and Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine and
Institute of Endocrinology, Prague, Czech Republic, 4Department of Clinical Endocrinology and Metabolism, University Medical Centre
Groningen, Groningen, the Netherlands, 5Department of Physiology, Obesity Center, Louis Mourier Hospital (APHP), Colombes and
Paris Diderot University, Paris, France, 6Endocrine, Cardiovascular & Metabolic Research, Unit for Multidisciplinary Research in
Biomedicine (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Oporto, Porto, Portugal, 7University College of
London, London, UK, 8Department of Endocrinology and Nutrition, University Clinic of Navarra, Pamplona, Spain, 9CIBEROBN, Instituto
Carlos III, Madrid, Spain, 10Obesity and Lipodystrophy Center, University Hospital of Pisa, Pisa, Italy, 11Division of
Endocrinology and Diabetology, Department of Medicine, Medical University of Graz, Graz, Austria, 12Department of
Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands, 13Department of Clinical
Endocrinology and Metabolism, Leiden University Medical Centre, Leiden, the Netherlands, and 14Department of
Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
Abstract
Obesity is an emerging condition, with a prevalence of ~20%. Although the simple measurement of BMI is likely a simplistic approach to obesity, BMI is easily calculated, and there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity. An increased BMI leads to a number of hormonal changes. Additionally, concomitant hormonal diseases can be present in obesity and have to be properly diagnosed – which in turn might be more difficult due to alterations caused by body fatness itself. The present European Society of Endocrinology Clinical Guideline on the Endocrine Work-up in Obesity
acknowledges the increased prevalence of many endocrine conditions in obesity. It is recommended to test all patients with obesity for thyroid function, given the high prevalence of hypothyroidism in obesity. For
hypercortisolism, male hypogonadism and female gonadal dysfunction, hormonal testing is only recommended if case of clinical suspicion of an underlying endocrine disorder. The guideline underlines that weight loss in obesity should be emphasized as key to restoration of hormonal imbalances and that treatment and that the effect of treating endocrine disorders on weight loss is only modest.
1. Summary of recommendations
The recommendations (R) in this guideline are worded as we recommend (strong recommendation) and we suggest (weak recommendation). We formally graded only the evidence underlying recommendations for diagnostic strategies. The quality of evidence behind the recommendations is
classified as very low (+000), low (++00), moderate (+++0) and strong (++++). See further section ‘Summary of methods used for guideline development’. Recommendations based on good clinical practice and/or experience of the panelists were not graded.
Correspondence should be addressed to R Pasquali Email renato.pasquali@unibo.it European Journal of Endocrinology (2020) 182, G1–G32
Clinical Practice
Guideline
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R.1.1. We suggest that for all patients it is of value to
measure weight and height to calculate BMI, as obesity is an important condition that often remains undiagnosed. For routine care defining obesity as BMI >30 kg/m2 is
sufficient as first diagnostic measure. Measuring waist-circumference can provide additional information especially if BMI <30 kg/m2.
R.1.2. We recommend that not all patients with obesity
are routinely referred to an endocrinologist.
R.1.3. We recommend that weight loss in obesity is
emphasized as key to restoration of hormonal imbalances.
R.1.4. We recommend taking into account drugs
and dietary supplements that interfere with hormone measurements as part of the hormonal evaluation in obesity.
R.2.1. We recommend that all patients with obesity are
tested for thyroid function (+++0).
R.2.2. We recommend that testing for hypothyroidism is
based on TSH; if TSH is elevated, free T4 and antibodies (anti-TPO) should be measured (++00).
R.2.3. We do not recommend the routine measurement
of FT3 in patients with elevated TSH.
R.2.4. We suggest that for obese patients the same normal
hormonal values are applied as for non-obese (+000).
R.2.5. We recommend that overt hypothyroidism
(elevated TSH and decreased FT4) is treated in obesity irrespective of antibodies (++00).
R.2.6. We recommend against the use of thyroid
hormones to treat obesity in case of normal thyroid function (++00).
R.2.7. We recommend that hyperthyrotropinaemia
(elevated TSH and normal FT4) should not be treated in obesity with the aim at reducing body weight (++00).
R.2.8. We suggest that for the decision to treat or not
to treat hyperthyrotropinaemia, TSH level, thyroid antibodies, and age should be taken into account.
R.2.9. We suggest against the use of routine ultrasound of
the thyroid gland irrespective of thyroid function.
R.3.1. We recommend that testing for hypercortisolism is
not routinely applied in obesity (++00).
R.3.2. In patients with clinical suspicion of
hypercortisolism biochemical testing should be performed (++00).
R.3.3. We recommend that in patients going for
bariatric surgery (testing for) hypercortisolism should be considered.
R.3.4. We suggest that for patients with obesity the same
normal values are applied as for non-obese (+000).
R.3.5. We recommend not to test for hypercortisolism in
patients using corticosteroids.
R.3.6. If hypercortisolism testing is considered, we
recommend a 1 mg overnight dexamethasone suppression test as first screening tool.
R.3.7. If the 1 mg overnight dexamethasone suppression
test is positive, we recommend a second biochemical test; this can be either 24-h urine cortisol or late-night salivary cortisol.
R.3.8. In all patients with confirmed hypercortisolism,
an ACTH should be measured and further imaging should be performed to find the cause/source of the hypercortisolism.
R.3.9. Treatment of proven endogenous hypercortisolism
is not normalizing BMI in most cases.
R.4.1. We recommend that biochemical testing for
hypogonadism is not routinely applied in male obese patients; we do recommend investigating key clinical symptoms/signs of hypogonadism (++00).
R.4.2. In male patients with obesity with clinical features
of hypogonadism we suggest measuring total and free testosterone (or calculated), SHBG, FSH and LH.
R.4.3. In obesity we suggest applying age-specific
reference ranges for testosterone (+000).
R.4.4. We recommend emphasizing the importance of
weight loss to restore eugonadism in obese patients with biochemical and clinical hypogonadism.
R.4.5. We suggest that if weight loss cannot be achieved
and if clinical and biochemical hypogonadism persists, treatment with testosterone can be considered in individual cases; contra-indications should be considered and other causes of hypogonadism should have been ruled out. The sole presence of obesity is not enough reason to start testosterone (+000).
R.4.6. We suggest treatment with testosterone aiming at
testosterone levels in the normal range (+000).
R.4.7. We suggest stopping testosterone treatment if
clinical features are not improving despite biochemical restoration for 6–12 months (+000).
R.4.8. We do not recommend testosterone treatment as
a first therapeutic measure in hypogonadal male patients with obesity seeking fertility (+000).
R.5.1. We recommend that testing for gonadal
dysfunction is not routinely applied in female patients with obesity (++00).
R.5.2. We suggest to assess gonadal function in female
patients with obesity with menstrual irregularities and chronic anovulation/infertility.
R.5.3. For evaluation of menstrual irregularity we suggest
to assess gonadal function by measuring LH, FSH, total testosterone, SHBG, Δ 4androstenedione, oestradiol, 17-hydroxyprogesterone and prolactin. If the menstrual
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cycle is irregular but somewhat predictable, we suggest that the assessment should take place during the early follicular phase.
R.5.4. For evaluation of anovulation we suggest gonadal
function to be assessed by measuring LH, FSH, oestradiol, progesterone and prolactin.
R.5.5. We recommend to assess androgen excess
when PCOS is considered based on the clinical features. We suggest to measure total testosterone, free T, Δ 4androstenedione and SHBG. We additionally recommend to assess ovarian morphology and blood glucose.
R.5.6. We suggest to initiate metformin treatment in
women with PCOS that additionally present metabolic syndrome features (++00).
R.5.7. We recommend not to start metformin with the
sole aim to reduce body weight (+000).
R.5.8. We recommend not to start oestrogen substitution
in postmenopausal obese women with the sole aim to reduce body weight (+000).
R.6.1. We recommend that testing for IGF1/GH is not
routinely applied in obesity (+000).
R.6.2. We suggest testing for IGF1/GH only in patients
with suspected hypopituitarism; if tested a dynamic test should be performed as a minimum (+000).
R.6.3. We recommend not to use GH to treat obesity in
patients with normal GH levels (+000).
R.6.4. We suggest not to perform routine tests for vitamin
D deficiency in patients with obesity (+000).
R.6.5. We suggest not to test for hyperparathyroidism
routinely in patients with obesity (+000).
R.6.6. We recommend not to test routinely other
hormones, such as leptin and ghrelin, unless there is suspicion of a syndromic obesity.
R.6.7. We suggest to consider secondary causes of
hypertension in the context of therapy-resistant hypertension in obesity.
2. Obesity – a short introduction
Obesity is an emerging condition and plays a central role in the development of non-communicable diseases like diabetes, hyperlipidaemia, hypertension, cardiovascular disease and cancer (1). Due to the tight relation with type 2 diabetes, the combination of the two diseases is often called ‘diabesity’ and treated accordingly (2). Following, it is important for obesity to become an integral part of medicine, and multidisciplinary European guidelines have been released (3).
The actual prevalence of obesity in most European countries is around 20% (3). The numbers have almost tripled since 1986 when the European Association for the Study of Obesity (EASO) was founded to address the emerging obesity problem (4). There is a clear heterogeneity in the prevalence; there is however no systematic difference in prevalence between men and women (5).
Prevalence data reveal only part of the problem as BMI has been used as single indicator of overweight and obesity. If one considers that unhealthy visceral fat and/or increased body fatness is also present in a substantial amount of normal – and overweight persons, the burden of unhealthy body fat with hormonal, metabolic and disease implications is even higher (6). Although the simple measurement of BMI is likely an overtly simplistic approach to obesity, we use a BMI-based definition of obesity (BMI >30.0 kg/m2)
throughout this guideline. The main reason is that BMI is easily calculated in clinical practice and also because there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity.
Increased body fatness leads to a number of hormonal changes, the most obvious example being insulin resistance. Additionally, concomitant hormonal diseases can be present and have to be properly diagnosed – which in turn might be more difficult due to alterations caused by body fatness itself. The two-way relationship between obesity and hormones, obesity as cause and consequence of hormonal alterations, is conceptually shown in Fig. 1. The main hormonal alterations in obesity are shown in
Table 1. Different diseases that potentially cause obesity are listed in Table 2.
The present European Society of Endocrinology Clinical Guideline is focused on the endocrine work-up in patients with obesity; although not its main focus we do discuss the potential therapeutic consequences of hormonal alterations in patients with obesity. We do not to focus on syndromic obesity.
3. Methods
3.1. Guideline working group
This guideline was developed by The European Society of Endocrinology (ESE). The chairs of the working group, Renato Pasquali and Olaf Dekkers (methodological expert), were appointed by the ESE Clinical Committee. Hermann
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Toplak served as representative of the European Association of the Study of Obesity (EASO). The multidisciplinary team consisted of the following experts: Renato Pasquali (Italy), Mariana P Monteiro (Portugal), Felipe Casanueva (Spain), Ferruccio Santini (Italy), Martin Haluzik (Czech Republic), Severine Ledoux (France), Javier Salvador (Spain), Hermann Toplak (Austria), Olaf Dekkers (Netherlands, methodology) and Leonie van Hulsteijn (Netherlands, methodology). The working group had two in-person meetings (February 2018 and September 2018). Consensus was reached upon discussion; minority positions were taken into account in the rationale behind recommendations.
3.2. Target group
This guideline was developed for healthcare providers involved in the care of patients with obesity, which covers a broad range of doctors. In line, the guidelines were not developed with the specific aim to cover rare forms of obesity.
3.3. Aims
The overall purpose of this guideline is to provide clinicians with practical guidance for the endocrine work-up in
obesity. In clinical practice, diagnostic – and treatment decisions should take into account the recommendations but also the clinical judgment of the treating physician. Recommendations are thus never meant to replace clinical judgment.
3.4. Summary of methods used for guideline development
The methods used have been described in more detail previously (11). In short, the guideline used GRADE (Grading of Recommendations Assessment, Development and Evaluation) as a methodological base. The first step was to define the clinical questions (see Section 3.5), the second a systematic literature search (see Section 3.6). The quality of evidence behind the recommendations is classified as very low (+000), low (++00), moderate (+++0) and strong (++++). Two problems hampered a formal grading of the evidence for endocrine testing in obesity: the lack of reference standard for most endocrine conditions in obesity; the presence of such reference standard is crucial when formally grading studies on diagnostics (12). Secondly, grading for diagnostic strategies is possible, it requires, however, that studies compare different Figure 1
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strategies with respect to clinical effectiveness and harms (12). Such studies have not been performed in obesity.
For the recommendations we took into account: (1) quality of the evidence, (2) balance of desirable and undesirable outcomes, (3) values and preferences (patient preferences, goals for health, costs, feasibility of implementation, etc.), (4) clinical experience of the panel (13, 14). The recommendations are worded as recommend (strong recommendation) and suggest (weak recommendation). The meaning of a strong recommendation can be stated as follows: reasonably informed persons (clinicians, politicians and patients) would want the management in accordance with the recommendation. For a weak recommendation, most persons would still act in accordance with the guideline, but a substantial number would not (14). Recommendations based on good clinical practice and experience of the panelists were not graded (15). Recommendations were derived from majority consensus of the guideline development committee.
All recommendations are accompanied by text explaining why specific recommendations were made.
3.5. Clinical questions, eligibility criteria and endpoint definition
The present guideline is primarily about the endocrine work-up in obesity, that is, about diagnostic questions. Although diagnostic strategies can be compared in a randomized trial (i.e. what diagnostic test is associated with the best morbidity and mortality outcome), to the knowledge of the panel no such trials in obesity were published. The guideline panel considered a systematic review on the prevalence of most common endocrine disorders in obesity to be relevant as evidence base for the guideline. A literature search and systematic review on the prevalence of thyroid disorders, autonomous cortisol secretion, hypogonadism (males) and hyperandrogenism (females) was subsequently performed (Table 3). This review is summarized below, and published as stand-alone paper (16).
Table 1 Hormonal alterations in obesity.
Hormone Levels in obesity Proposed pathophysiologic mechanism
TSH N or ↑ ↑ leptin and insulin
↑ peripheral T4 disposal
FT4 N or slightly ↓ ↑ disposal
Cortisol (blood and urine, salivary) N or ↑
Altered suppression tests ↑ CRH, ↑ adipose 11-HSD, ↓ CBGHyperactivity of the HPA axis
ACTH N or ↑ ↑ CRH
Growth hormone N or ↓ ↓ GHRH, ↑GH-BP, ↑insulin, ↓ghrelin, ↑somatostatin
IGF-1 N or ↓ ↑ GH sensitivity
Increased intrahepatic triglyceride content
Prolactin ? Discordant data
Testosterone (male) ↓ ↓ SHBG ↑ aromatase ↓GnRH
Testosterone (female) ↑ Insulin resistance (PCOS) ↓ SHBG
LH/FSH ↓ in men
↑ LH in women ↑ oestrogens/androgensInsulin resistance
25-OH vitamin D ↓ Trapping in adipose tissue, ↓ sun exposure
↓ 25OH vitamin D binding protein ↓ liver synthesis
PTH N or ↑ Secondary due to vitamin D deficiency
Insulin ↑ Insulin resistance
Renin ↑ ↑ Sympathetic tone
Aldosterone ↑ ↑ Adipokines, renin- angiotensin, leptin
GLP-1 ↓ ↑ FFA, microbiota
Leptin ↑ Increased adipose mass, Leptin resistance
Ghrelin ↓ Lack of ghrelin decrease after meals
11-HSD, 11β-hydroxysteroid dehydrogenase; ACTH, adrenocorticotropic hormone; CBG, corticosteroid-binding globulin; CRH, corticotropin-releasing hormone; FFA, free fatty acids; FSH, follicle-stimulating hormone; FT4, free thyroxine; GH-BP, growth binding protein; GHRH, growth hormone-releasing hormone; GLP, glucagon-like peptide; GnRH, gonadotropin-hormone-releasing hormone; HPA, hypothalamic–pituitary–adrenal axis; IGF, insulin-like growth factor; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; PTH, parathyroid hormone; SHBG, sex hormone-binding globulin; TSH, thyroid-stimulating hormone.
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Table 2 Examples of endocrine diseases/disturbances causing or contributing to obesity.
Condition Prevalence in obesity When to think about it First diagnostic procedure
Androgen deficiency (men) Common Severe obesity
Symptoms and signs of hypogonadism
LH FSH testosterone
Androgen excess (women) Common Central obesity
Irregular menses Hirsutism
Acanthosis nigricans
LH FSH oestradiol testosterone
Cushing’s disease or Cushing’s
syndrome Rare Central obesityHypertension
Type 2 diabetes
1 mg ODST Drug-induced endocrine dysfunction
(e.g. lithium, anti-depressants, antipsychotics, glucocorticoids…)
Common Psychiatric disorders
Glucocorticoid therapy 1 mg ODST to exclude Cushing syndrome (except in glucocorticoid use)
Ovarian failure (premature or
menopause) Premature uncommon
Physiological (Menopause) Common
Secondary amenorrhea Vasomotor symptoms
Vaginal mucosa atrophy
FSH, LH, oestradiol
GH deficiency Rare Hypothalamic or pituitary disease,
pituitary or hypothalamic surgery or radiation therapy
Serum IGF-I, GH-stimulating tests
Hypopituitarism Rare Suspicion of hypothalamic obesity
Surgery or radiotherapy in pituitary region
FT4 TSH LH FSH (testosterone or estradiol)
GH IGF-1 PRL ACTH stimulation test GH stimulation test Hypothalamic obesity associated with
Genetic Syndromes Extremely rare Hypogonadism (hypogonadism or hypergonadotropic) or variable gonadal function. dysmorphic syndrome, mental and grow retardation
Leptin (leptin resistance) (7); genetic testing
Hypothalamic obesity acquired
(hypothalamic lesions or, tumors) Rare Severe hyperphagiaPossible multiple endocrine abnormalities
Brain CT or MRI
(Severe) hypothyroidism Rare Mixedematous features
Concurrent autoimmune diseases FT4 TSH
Insulinoma Very rare Hypoglycaemic symptoms Blood glucose, insulin, C-peptide
72-h supervised fast
Leptin deficiency Extremely rare Severe childhood obesity Leptin ↓
Leptin receptor deficiency or inactive
leptin (8) Extremely rare Severe childhood obesity Leptin ↑
MC4R mutation rare Severe childhood obesity Leptin normal or ↑
Primary empty sella Rare (increase
intracranial pressure)
female, HTA, SAOS headache,
menstrual disturbances Prolactin, FSH LH, testosterone/oestradiol, cortisol, IGF-1 MRI of pituitary
Abnormal processing of
Propiomelanocortin (POMC) gene mutations
Extremely rare Severe childhood obesity
Red hair ACTH ↓ (9)
Prohormone convertase 1/3 deficiency (PC-1/3) (PCSK1 gene mutation)
Extremely rare Multiendocrine disorders, including diabetes insipidus, growth hormone deficiency, primary hypogonadism, adrenal insufficiency and
hypothyroidism (10) Pseudohypoparathyroidism Type 1a
(Albright hereditary osteodystrophy)
Rare Short stature, short fourth
metacarpal bones, obesity, s.c. calcifications, developmental delay
PTH ↑ calcium ↓ phosphate ↑
ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; FT4, free thyroxine; GH, growth hormone; IGF, insulin-like growth factor; LH, luteinizing hormone; MC4R, melanocortin receptor 4; ODST, overnight dexamethasone suppression test; PCSK, proprotein convertase subtilisin/kexin; PTH, parathyroid hormone; TSH, thyroid-stimulating hormone.
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3.6. Description of search and selection of literature
A literature search of electronic medical databases was performed. We only considered papers with >10 patients included, as obesity is not a rare condition and studies with <10 patients probably suffer from selection bias. For all papers considered obesity was defined as BMI ≥30 kg/m2 and/or large waist circumference as expression of
abdominal obesity (definition of enlargement based on different criteria used in included articles). Overall, 3819 potentially relevant papers were considered; 68 were included (two studies assessed both hypothyroidism and hypercortisolism (16)).
3.7. Review process and endorsement of other societies
A draft of the guideline was reviewed by the experts in the field; it was also submitted for comments by ESE members. All comments and suggestions were then discussed and implemented as appropriate by the panel.
4. Summary of results from the
systematic review
For details of the review see (16). In summary, the prevalence of hypothyroidism in obesity was 14.0% (95% CI: 9.7–18.9), based on 19 studies; the prevalence of subclinical hypothyroidism was found 14.6% (95% CI: 9.2–20.9), also based on 19 studies. For both clinical and subclinical hypothyroidism, the reported prevalence ranged considerably between included studies, suggesting underlying clinical heterogeneity.
For hypercortisolism, we found an overall low prevalence of 0.9% (95% CI: 0.3–1.6), based on 22 studies. For male hypogonadism, based on free testosterone measurements, the pooled prevalence was found to be 32.7% (95% CI: 23.1–43.0); the reported prevalence in the 11 included papers ranged from 16 to 52%, also suggesting underlying heterogeneity. For hyperandrogenism in females, reported prevalences of PCOS ranged from 9.1 to 25% (three studies), which is higher than expected (17).
Table 3 Clinical questions and metrics of the review.
Clinical question Population Predefined selection criteria and key outcome parametersRestriction Outcome studies includedNumber of Question 1A: What is the
prevalence of overt hypothyroidism in obesity?
Question 1B: What is the
prevalence of subclinical hypothyroidism in obesity?
Obese patients Data on subclinical/overt hypothyroidism based on raised TSH (definition of positive test based on cut-off values used in included articles)
Prevalence of subclinical/overt hypothyroidism
27
Question 2: What is the
prevalence of hypercortisolism in obesity?
Obese patients Data on hypercortisolism based on ≥2 of the following measurements: UFC greater than the normal range for the assay, elevated LNSC, elevated serum cortisol after ODST or after LDDST (definition of positive test based on cut-off values used in included articles)
Prevalence of
hypercortisolism 22
Question 3: What is the
prevalence of hypogonadism in male patients with obesity?
Obese male
patients Data on hypogonadism based on low TT or FT (definition of positive test based on cut-off values used in included articles)
Prevalence of
hypogonadism 18
Question 4: What is the
prevalence of hyperandrogenism in female patients with obesity?
Obese female
patients Data on hyperandrogenism based on raised TT or FT (definition of positive test based on cut-off values used in included articles)
Prevalence of
hyperandrogenism 3
BMI, body mass index; FT, free testosterone; LDDST, low-dose dexamethasone suppression test; LNSC, late night salivary cortisol; ODST, overnight dexamethasone suppression test; TSH, thyroid-stimulating hormone; TT, total testosterone; UFC, urine free cortisol; WC, waist circumference.
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5.1. General recommendations
R.1.1. We suggest that for all patients it is of value to measure weight and height to calculate BMI, as obesity is an important condition that often remains undiagnosed. For routine
care defining obesity as BMI >30 kg/m2 is
sufficient as first diagnostic measure. Measuring waist-circumference can provide additional
information especially if BMI <30 kg/m2.
Reasoning:
Obesity, defined by a BMI >30 kg/m2, is in most cases
associated with high fat mass and thus BMI is considered an adequate indicator of obesity and sufficient as first diagnostic measure. Furthermore, a grading in obesity I (>30 kg/m2), obesity II (>35 kg/m2) and obesity III (>40
kg/m2) is proposed and should be used in clinical practice.
Recently, EASO has suggested to grade further with obesity IV-VI accordingly (6) because of the increasing prevalence of obesity related complications with more severe obesity. Especially in subjects with BMI <30 kg/m2 increased body
fat mass (with sarcopenia) may be suggested by increased waist circumference (in Caucasian females a waist <80 cm is regarded normal, 80-88 cm as elevated and >88 cm is regarded equally important as a BMI >30 kg/m2, in males
the respective cut-offs are 94 and 102 cm). In clinical practice these measures can be easily achieved. Detailed phenotyping may include BIA (Bioelectrical impedance analysis) measurements, DXA (Dual-energy X-ray absorptiometry) Scans or BOD-POD (air displacement plethysmography) measurements (3).
R.1.2. We recommend that not all patients with obesity are routinely referred to an endocrinologist.
Reasoning:
In most cases, despite obesity being a condition of endocrine and metabolic imbalance, obesity is not caused by other endocrine diseases or hormonal disturbances. Furthermore, the prevalence of obesity is such that standard referral to an endocrinologist would not be compatible with available resources in most countries. The endocrinologist should be consulted in case of clear suspicion of an endocrine disease (e.g. endogenous hypercortisolism, hypogonadism in males or androgen excess in women). In addition, because the prevalence of endocrine disturbances is related to obesity severity, and because clinical signs and symptoms of endocrine conditions can be difficult to distinguish from obesity, we suggest that in patients with morbid obesity a referral
to an endocrinologist is considered. Further reasons for referral to the endocrinologist include therapy-resistant obesity and /or rapid weight gain and candidates for bariatric surgery.
R.1.3. We recommend that weight loss in obesity is emphasized as key to restoration of hormonal imbalances.
Reasoning:
For most hormones (TSH, cortisol. testosterone), the proper equilibrium is usually restored following weight reduction, irrespective of therapeutic strategy (see following chapters for details).
R.1.4. We recommend taking into account drugs and dietary supplements that interfere with hormone measurements as part of the hormonal evaluation in obesity.
Reasoning:
Beside general drugs used to manage obesity complications, several dietary supplements are commonly taken by patients with obesity, with the aim of facilitating weight loss or well-being, controlling glucose metabolism or preventing cardiovascular events. Some of these exogenous substances may interfere with the regulation of various hormonal axes as well as with hormonal assays (2, 18, 19).
5.2. Testing for thyroid function
R.2.1. We recommend that all patients with obesity are tested for thyroid function (+++0). Reasoning:
Thyroid function is commonly assessed, independently of obesity, because hypothyroidism is one of the most common endocrine diseases. In Europe, the prevalence of overt hypothyroidism varies between 0.2 and 5.3% (20) and that of subclinical hypothyroidism between 4 and 10% (21); the prevalence of undiagnosed hypothyroidism in Europe was estimated around 5% (22).
Symptoms of hypothyroidism (such as fatigue, depression, cramps, menstrual disturbance or weight gain) are nonspecific (23) and can be confused with those of obesity. Hypothyroidism can be easily diagnosed by blood tests. Screening of the general population is mostly not recommended (24), although some populations at risk, have been identified; interestingly, obesity is not among these conditions (20, 24), but the usefulness to test TSH in obesity was recently suggested (25). Furthermore,
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TSH screening is recommended in patients with severe obesity before bariatric surgery. A higher prevalence of subclinical hypothyroidism in obesity has been shown. Notably, one study noted a tenfold increase of either overt or subclinical hypothyroidism compared to the general population (26). In our meta-analysis (16), the prevalence of hypothyroidism in obesity was 14.0% (95% CI 9.7– 18.9); the prevalence of subclinical hypothyroidism was found 14.6% (95% CI 9.4–20.9).
Thyroid function is frequently assessed in patients with obesity with the hope to identify a cause of obesity and/or a reason for resistance to weight loss efforts. Certainly, thyroid hormones have an important role in energy metabolism and hypothyroidism could indeed induce weight gain by means of both an increasing fat mass, due to mild decrease in resting energy expenditure and reduced physical activity, and also fluid retention, due to glycosaminoglycans accumulation (20, 27). However, despite weight gain being a frequent complaint in hypothyroidism (28), it is usually of limited extent (27). In line, treatment of overt hypothyroidism produces only a modest weight loss (usually of less than 10%) (29, 30, 31), indicating that severe obesity is usually not secondary to hypothyroidism. Several studies have shown a positive association between TSH and BMI (32, 33) and some studies suggested that small variations of thyroid hormones, even in the normal range, may promote weight gain (34) or impair weight loss induced by diet (35) or bariatric surgery (36). However, some longitudinal studies suggest that changes in thyroid hormones are side effects of increasing body weight (BW) rather than the cause (37). Furthermore, abnormal thyroid function usually improves after weight loss obtained by calorie restriction (38, 39) or by bariatric surgery (21, 36). This suggests that in obesity the increase in serum TSH (in the absence of thyroid autoantibodies) is likely an adaptive response (40) rather than the primary event (see also 5.2.4) (41). Thus, hyperthyrotropinaemia associated with obesity must be differentiated from auto-immune-related subclinical hypothyroidism.
No study directly assessed the benefits and harms of screening versus no screening in obese populations (42). However, if ‘true’ hypothyroidism is present, it potentiates the risk of obesity to develop cardiovascular risk factors and features of metabolic syndrome (21). Hypothyroidism contributes to an unfavorable lipid profile, and thus, potentially increases vascular risk (43, 44). Finally, untreated hypothyroidism could blight the attempts at loosing body weight.
In conclusion, because hypothyroidism is rather prevalent and could potentiate weight gain and worsen comorbidities in obesity, and because assessment is simple and treatment is inexpensive and safe, we recommend to assess thyroid function in obesity.
R.2.2. We recommend that testing for hypothyroidism is based on TSH; if TSH is elevated, free T4 and antibodies (anti-TPO) should be measured (++00).
Reasoning:
According to American guidelines (45), TSH is the best screening test for thyroid dysfunction for the vast majority of clinical situations, in which normal TSH is enough to rule out primary hypothyroidism. Central hypothyroidism, with low-to-normal TSH concentrations and a disproportionately low concentration of fT4, is rare representing less than 1% of cases of hypothyroidism (46). Thus, fT4 has to be measured only if TSH is elevated or if disorders other than primary hypothyroidism are suspected, notably if there is a suggestion of pituitary disease, thyroid hormone resistance syndrome, or symptoms of hypothyroidism with normal TSH (46). In these situations, free T4 should be measured instead of total T4 (45).
The most common cause of hypothyroidism is chronic autoimmune thyroiditis. Raised concentrations of thyroid antibodies are detected in about 11% of the general population (47), while studies in obesity have provided conflicting results (48, 49). Thyroid antibody profiles are helpful to diagnose autoimmune hypothyroidism and to determine patients at risk of developing hypothyroidism. In patients with increased TSH, thyroid peroxidase (TPO) antibodies can predict progression to overt disease, with TPO antibodies levels >500 IU/mL indicating an increased risk to progress (27, 49). Thus, assessment of TPO antibodies is recommended in case of subclinical hypothyroidism (45). Although there is discussion about the value of thyroglobulin antibodies (25), especially in the context of obesity, the evidence is currently too weak to recommend testing for thyroglobulin antibodies (50); in individual cases, thyroglobulin testing can be considered.
R.2.3. We do not recommend the routine measurement of FT3 in patients with elevated TSH.
Reasoning:
Measurement of total or free triiodothyronine (T3) is not useful to detect hypothyroidism (20) as levels are
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often normal due to hyperstimulation of the remaining functioning thyroid tissue by elevated TSH. Moreover, FT3 level is difficult to interpret because many acute or chronic extra-thyroidal conditions (involving nutritional status and systemic inflammation) can reduce the conversion of T4 to T3, a mechanism known as ‘non-thyroidal illness’, ‘euthyroid sick syndrome’ or ‘low-T3 syndrome’ (51). There are very few data on the incidence of non-thyroidal illness in the obese population but one publication suggested that inflammation may increase non-thyroidal illness in obesity (52). In contrast, FT3 has been described to be higher in obesity than in lean people, this being mainly related to the nutritional status (53). This shows that the interpretation of FT3 in obesity is not straightforward.
R.2.4. We suggest that for obese patients the same normal hormonal values are applied as for non-obese (+000).
Reasoning:
The definition of hypothyroidism is based on statistical reference ranges (20, 45), the reference range for third-generation TSH assays being laboratory specific. This upper limit is typically around 4 mIU/L in the general population (45). Obesity is associated with modifications of thyroid parameters: TSH levels are usually higher than in normal-weight, age- and gender-matched individuals and are correlated with BMI (48). The relation of BMI with FT3 and FT4 is inconsistent, but a negative relation between BMI and FT4 and a positive relation between BMI and FT3 with a decrease FT4/FT3 ratio have been described (48, 53). The TSH elevation could reflect decrease in thyroid hormones concentrations, explained by an increased plasmatic volume or increased rate of thyroid hormone disposal in obesity, causing in turn a compensatory activation of the pituitary–thyroid axis (54). This interpretation is in line with lower FT4 levels in obesity, together with the need for higher doses of substitutive l-thyroxine in hypothyroid patients with obesity. Other mechanisms proposed to explain these modifications include increases in leptin and insulin (27).
Some authors argue for specific norms in obesity. Notably, in a large cross-sectional study, TSH ranges were estimated as 0.6–5.5 mIU/L in the normal-weight category and 0.7–7.5 mIU/L in the morbid obesity category. This study showed that, by using the normal-weight ranges, the prevalence of high TSH levels increased threefold in the morbid obesity category (53). However, no compelling evidence has been provided that using specific reference values for the obese population would
help to identify patients with thyroid dysfunction who need treatment.
R.2.5. We recommend that overt hypothyroidism (elevated TSH and decreased FT4) is treated in obesity irrespective of antibodies (++00).
Reasoning:
Although the issue is still controversial (55), treatment with levothyroxine substitution should be considered in case of overt hypothyroidism, or in mild hypothyroidism with TSH >10 mIU/L, in line with current guidelines (45). L-thyroxine is the hormone of choice; no additional benefits have been demonstrated of L-thyroxine and L-triodothyronine combination (56). If laboratory-specific normal values are not available, a TSH target of 0.45–4.12 mIU/L should be considered (45). The initial l-thyroxine dose should be assigned on the basis of the thyroid hormone levels and clinical situation (45) and subsequently adjusted by periodic assessment of serum TSH. FT3 and FT4 measurement are not recommended for treatment monitoring. Caution in the choice of the starting dose and in dose escalation should be used in patients with long-lasting, overt hypothyroidism, particularly the elderly and/or with cardiovascular disease.
In obesity, treatment of hypothyroidism is followed by a mild increase in resting energy expenditure (34) but only a modest weight loss is achieved (29), mainly determined by excretion of excess body water. The target of TSH is the same as in the general population and should not be adjusted with the aim at reducing BMI. The l-thyroxine dose is usually to be reduced after weight loss achieved by bariatric surgery (57).
R.2.6. We recommend against the use of thyroid hormones to treat obesity in case of normal thyroid function (++00).
Reasoning:
Thyroid hormone preparations and their derivatives have been extensively employed in the past century as anti-obesity drugs (the first clinical reports on the weight-lowering effect of sheep-derived thyroid extracts date from the 1890s) and sometimes are still inappropriately prescribed, despite specific recommendations against their use in euthyroid obese subjects (45). The rationale for this misuse stems from the well-known link between thyroid hormones and resting energy expenditure, which in popular fallacy is often translated into a link between hypothyroidism and obesity. Furthermore, the reduction in FT3 levels during caloric deprivation has been advocated as a possible cause for failure of hypocaloric diets. Several
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studies have been performed to investigate the ability of thyroid hormone or their analogues to favour weight loss, without producing adverse effects due to iatrogenic thyrotoxicosis (58, 59, 60). Overall, these studies have demonstrated only minor effects in terms of efficacy, while increased urinary nitrogen excretion has been observed, indicating loss of fat-free tissue beside the occurrence of adverse effects on bone metabolism and affective status. Furthermore, excessive thyroid hormone in patients with obesity already at risk for cardiovascular disease may facilitate the onset of cardiac arrhythmia, heart failure or ischemic events (61). Apart from decreasing body weight, thyroid hormone also improves hepatic lipid metabolism, which was also used as an argument for use in obesity. The development of TRβ-selective agonist supposed to improve metabolic parameters without affecting heart rate did not have a conclusive outcome and the combined peptides that deliver FT3 specifically in the liver are not yet developed (62).
R.2.7. We recommend that hyperthyrotropinaemia (elevated TSH and normal FT4) should not be treated in obesity with the aim at reducing body weight (++00).
Reasoning:
A slightly increased TSH (<10 mIU/L) in the presence of normal FT4 is a common finding in obesity, and on its own is not enough to diagnose a condition of primary hypothyroidism. The Whickham survey estimated that annual progression of subclinical hypothyroidism to overt hypothyroidism occurs in 2–5% (63) and the rate may be lower in obesity (64). Very few clinical trials have studied the potential benefits and the safety of l-thyroxine treatment in the obese population. Randomized controlled trials reported no relevant difference in BMI with levothyroxine treatment compared with placebo in subclinical hypothyroidism (42). A recent meta-analysis showed that treatment of subclinical hypothyroidism does not improve clinical symptoms such as overweight or quality of life (65). Harms of treatment were poorly studied and sparsely reported, and low TSH values are frequently found in patients treated with l-thyroxine potentially causing side effects. Indeed, between 10 and 33% of individuals on l-thyroxine therapy have TSH values below normal and approximately one third to one half of these TSH levels are less than 0.1 mIU/L (66).
Patients with obesity often complain of symptoms suggestive of hypothyroidism that may prompt the practitioner to introduce thyroid hormone treatment.
As argued, thyroid hormone treatment should not be initiated only based on the finding of hyperthyrotropi-naemia, since weight loss is unlikely and may deter the patient seeking appropriate management of their obesity.
R.2.8. We suggest that for the decision to treat or not to treat hyperthyrotropinaemia, TSH level, thyroid antibodies, and age should be taken into account. Reasoning:
A more pronounced elevation of TSH is related to higher risk of developing hypothyroidism (67). Although there is a general agreement that hypothyroidism with TSH levels above 10 mIU/L should be treated (45), whether and which patients with TSH levels of 4.5–10 mIU/L benefit is less certain. For the decision on starting treatment of mild hypothyroidism other considerations should be taken into account. The presence of thyroid autoimmunity (see 5.2.2), or coexistence of other causes of primary hypothyroidism (e.g. previous radioiodine treatment for hyperthyroidism or a history of destructive thyroiditis), particularly in a young subject or in a woman in fertile age should prompt l-thyroxine treatment. By contrast, older age (>70 years) particularly in the presence of concurrent (cardiovascular) diseases, should direct the decision toward a follow-up strategy (45). l-thyroxine replacement therapy is recommended for older patients in good health status with TSH >10 mIU/L (68). The link between mild hypothyroidism and coronary heart disease is generally observed in the youngest population only and on the contrary, cohort studies have demonstrated that extreme longevity is associated with higher TSH levels (68). In addition, in the ‘Trust Thyroid Trial’, levothyroxine provided no apparent benefits on clinical symptoms in older persons with subclinical hypothyroidism (69), but no specific trial was performed in old obese persons.
Among women of reproductive age, subclinical hypothyroidism has been associated with infertility, an increased risk of adverse pregnancy and neonatal outcomes, and possibly with an increased risk of neurocognitive deficits in offspring. There is evidence that T-thyroxine therapy decreases the risk for pregnancy loss and preterm delivery in pregnant women with TSH >4.0 mIU/L (70). The ATA recommendations propose to treat women of childbearing age who are pregnant or planning a pregnancy, if they have positive levels of serum TPOAb and their TSH is >2.5 mIU/L (45). During pregnancy, the target range for TSH should be based on trimester-specific ranges (around 2.5 mIU/L, 3 mIU/L and 3.5 mIU/L at the first, second and third trimester, respectively). However,
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no study was specifically conducted in obese women to ensure that the same targets are to be achieved.
R.2.9. We suggest against the use of routine ultrasound of the thyroid gland irrespective of thyroid function.
Reasoning:
Autoimmune thyroiditis is often characterized by a hypoechogenic pattern on thyroid ultrasonography. Features of thyroiditis on ultrasound have the same predictive value as TPO antibodies for progression from subclinical to overt hypothyroidism in women (71). Generally, in the absence of additional clinical indications such as abnormal thyroid palpation, an ultrasound is not required neither in overt (20) nor in subclinical hypothyroidism (21). In addition, given the high frequency of thyroid nodules, up to 50% by the age of 60 years, systematic ultrasound examination of the thyroid can lead to unnecessary invasive and expensive acts (72). In addition to biochemical changes, structural changes of the thyroid have also been associated with obesity. These include increases in thyroid volume and hypoechogenicity as well as thyroid nodules (27, 73), which may be due to increased TSH stimulation or increase in inflammatory mediators produced by the adipose tissue (27). The improvement of thyroid hypoechogenicity after bariatric surgery argues for this hypothesis (74).
An increased incidence of thyroid cancers in patients with obesity or insulin resistance has been reported. A recent meta-analysis of 21 articles has shown a 55% greater risk of thyroid cancer in patients with obesity. Each 5-unit increase in BMI was associated with 30% greater risk of thyroid cancer and both general and abdominal adiposity increased the risk. Obesity was positively related to papillary, follicular and anaplastic thyroid cancers, but negatively with medullary thyroid cancer (75). The impact of obesity on thyroid cancer aggressiveness has still to be defined (76). Importantly, data showing that early detection of thyroid cancer by systematic ultrasound assessment improve the prognosis of thyroid cancer in patients with obesity are lacking. In conclusion, despite a greater incidence of morphological abnormalities and thyroid cancers in obesity, there is no sufficient data in the literature to recommend systematic ultrasound assessment in obesity.
5.3. Testing for hypercortisolism
R.3.1. We recommend that testing for hypercorti-solism is not routinely applied in obesity (++00).
Reasoning:
Obesity is commonly listed among the different entities of so-called pseudo-Cushing states (77, 78). When central obesity is present, accompanied by some specific signs and associated cardiovascular risk factors such as hypertension and/or type 2 diabetes, a diagnosis of Cushing’s syndrome (CS) should be ruled out. The interest of unmasking endogenous hypercortisolism derives from its catabolic effects and devastating complications affecting quality of life and life expectancy unless properly treated (79). From a diagnostic perspective, difficulties arise to differentiate central obesity with associated comorbidities from mild CS. Despite a previous study has shown a prevalence of CS of 9.3% among a series of 150 patients with obesity (80), in most series the diagnosis of CS in obesity has been very uncommon, ranging from 0 to 0.7%, though patients with severe obesity have been included (81, 82). In our review the pooled prevalence of CS in obesity was estimated 0.9% (95% CI: 0.3–1.6) (16). On the other hand, a higher CS prevalence of ~2–3% in patients with type 2 diabetes with poor metabolic control has been shown (83, 84, 85). Moreover, subclinical CS has been reported to be more common in patients with obesity than in the general population (86), though its diagnostic criteria and treatment program have not been well established yet.
Assuming the epidemic proportions of obesity, its multifactorial origin and the low prevalence of CS among patients with obesity, the reported data do not lend support for a routine screening of CS in patients with obesity, according with previous recommendations (87). Therefore, screening for CS should be performed in patients who exhibit other specific features of hypercortisolism besides obesity.
R.3.2. In patients with clinical suspicion of hypercortisolism biochemical testing should be performed (++00).
Reasoning:
Screening for CS diagnosis in patients with obesity, should be carried out in subjects who exhibit specific clinical features suggestive of hypercortisolism. In this context, catabolic signs such as skin atrophy, osteoporosis, spontaneous ecchymoses, proximal myopathy or wide purple striae increase the likelihood of CS (77, 78, 88). The combination of some catabolic manifestations such as osteoporosis, spontaneous ecchymoses and thin skin is associated with a 95% probability of a diagnosis of CS (88). Other features such as central obesity, type 2 diabetes, hypertension or depression appear in CS but also are common in obesity (Table 4). These observations
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underline the importance of clinical assessment to determine which patients should be screened for CS diagnosis. The presence of uncontrolled hypertension and/or type 2 diabetes despite conventional therapy in young patients with abdominal obesity may also raise the possibility of CS and justify the screening for detection of hypercortisolism (78). Other features that may increase the probability of CS are nephrolithiasis, frequent infections and hypokalaemia, though are less specific than catabolic manifestations (Table 4).
R.3.3. We recommend that in patients going for bariatric surgery (testing for) hypercortisolism should be considered.
Reasoning:
Candidates to bariatric surgery commonly present with obesity-related comorbidities such as hypertension, metabolic syndrome and type 2 diabetes, which are also frequent in CS. Despite CS being a very rare disease, eventually some candidates to bariatric surgery may have endogenous hypercortisolism that could lead to severe adverse effects after surgery if undiagnosed (89). Factors such as hypercoagulability, catabolic state and increased cardiovascular risk may be responsible for severe postoperative complications, making this scenario especially sensible for CS detection (90).
Although the prevalence of CS in patients with severe obesity is generally low (81, 82, 91), a study of 16
patients operated of bariatric surgery has shown that CS diagnosis, persistence or recurrence was unrecognised, suggesting that CS may be responsible for less than expected improvement in hypertension and diabetes control as well as intense weight regain after bariatric surgery (92). Therefore, particular attention should be paid to patients who are candidates to bariatric surgery to rule out a diagnosis of CS, especially if suspicious clinical features are present (Table 4). Although biochemical preoperative screening for CS in all severe obesity patients is controversial (93), in candidates to bariatric surgery special attention to rule out CS in patients with suspicious clinical signs is needed to prevent potential surgical complications or adverse clinical outcomes following surgery.
R.3.4. We suggest that for patients with obesity the same normal values are applied as for non-obese (+000).
Reasoning:
Some experimental and clinical data points to a dysregulation in the activity of HPA axis in some patients with abdominal obesity, including excessive cortisol response to physical and psychological stimuli, reduced glucocorticoid feedback sensitivity and increased activity of 11-beta hydroxysteroid dehydrogenase in adipose tissue (94). However, other factors such as chronic stress may also be involved and hair cortisol measurement, Table 4 Clinical features of hypercortisolism in obesity.
Obesity Hypercortisolism Mechanisms
Wide purple striae No Yes Catabolic effect
Easy bruising No Yes Catabolic effect
Thin skin No Yes Catabolic effect
Proximal myopathy No Yes Catabolic effect
Osteoporosis No Yes Catabolic effect
Dorsocervical fat pad No Yes Fat redistribution
Facial plethora and
supraclavicular fullness No Yes Fat redistribution
Peripheral oedema No Yes Increased fluid reabsorption
Hyperandrogenism and/or
menstrual abnormalities Often present in obesity associated with polycystic ovarian syndrome Yes Gonadotrophin inhibition and increased androgen secretion Erectile dysfunction, infertility Often present in obesity without
associated hypercortisolism Yes Gonadotrophin inhibition
Truncal fat distribution (face,
neck, abdomen) Often present in obesity without associated hypercortisolism Yes Fat redistribution
Type 2 diabetes Often present in obesity without
associated hypercortisolism Yes Hyperglycaemic effect
Hypertension and/or past history
of cardiovascular disease Often present in obesity without associated hypercortisolism Yes Increased circulating volume and catecholamine sensitivity Depression, insomnia, irritability,
cognitive impairment, psychosis Often present in obesity without associated hypercortisolism Yes Hypercortisolism effects on the brain Incidental adrenal mass Often present in any patient Not always Potential origin of Cushing Syndrome Weight gain with growth
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when available, may offer a better reflection of chronic cortisol exposure than plasma or salivary samples (95).
Most studies rely on 1 mg late-night dexamethasone suppression as the screening method to detect CS in obesity. Despite that subjects with abdominal obesity may display less cortisol suppression in some cases, the vast majority of authors consider that this test shows an acceptable performance to rule out CS (78, 87, 95). Special attention should be paid to the simultaneous use of drugs that may disturb dexamethasone metabolism leading to potential false results (78). Although some studies have tested different cut-off points for cortisol suppression and diverse dexamethasone doses, there is no solid evidence to use different methodology or interpretation criteria from those considered in normal body weight. Likewise, there are no reasons to consider different cut-offs to evaluate nocturnal salivary cortisol or other functional HPA function parameters in patients with obesity.
R.3.5. We recommend not to test for hypercortisolism in patients using corticosteroids. Reasoning:
Exogenous corticosteroid therapy interferes with HPA axis assessment, by inducing cushingoid clinical features and suppressed endogenous HPA axis activity. Guidelines recommend investigating whether patients are on glucocorticoid treatment before starting evaluation for potential endogenous CS (78, 87, 95). In cases of exogenous corticosteroid therapy, the main interest is usually focussed on the impairment or recovery of HPA function rather than on the diagnostic possibility of endogenous CS.
R.3.6. If hypercortisolism testing is considered, we recommend a 1 mg overnight dexamethasone suppression test as first screening tool.
Reasoning:
A 1 mg overnight dexamethasone suppression test is simple, well standardized and used in the majority of previous studies (79). The risk of false-positive tests in severely obese patients is increased, but the specificity is still relatively high even in patients with severe obesity (92% in a recent study) (81). This test is sufficiently sensitive to rule out hypercortisolism with the threshold of post dexamethasone levels ≤50 nmol/L (≤1.8 µg/dL) or equivalent method-dependent cut-off value (96). A recent study did not find significant advantage of using 2 mg vs 1 mg suppression test in patients with obesity (97). In line, a study has shown that adjustment of the dexamethasone dose to body weight does not seem to substantially improve the sensitivity of the test, even in
individuals with obesity, particularly when near-maximal doses are administered. In addition, an effect of sex on post-dexamethasone cortisol concentrations, suppression of the HPA axis, and dexamethasone levels has been found, which may be dependent on differences in both cortisol and dexamethasone metabolism. On the other hand, at least in women, abdominal fat distribution may partially counteract the progressively greater suppressibility of the HPA axis that would be expected according to increasing BMI (98).
R.3.7. If the 1 mg overnight dexamethasone suppression test is positive, we recommend a second biochemical test; this can be either 24-h urine cortisol or late-night salivary cortisol. Reasoning:
The positivity of 1 mg overnight dexamethasone suppression test can be influenced by the presence of other comorbidities such as depression (99), alcoholism (100) and obstructive sleep apnoea (101) that are common in patients with obesity. Therefore, additional biochemical tests are needed in particular in patients with borderline cortisol post dexamethasone levels (between 51 and 138 nmol/L (1.9–5.0 µg/dL) (see ESE guideline management of adrenal incidentaloma for further information (96)). Confirmation of endogenous hypercortisolism requires the combination of different tests of adrenal function as recommended by the Endocrine Society guidelines (78). We suggest that after a 1 mg overnight dexamethasone suppression test, urinary-free cortisol (UFC) or/and late-night salivary cortisol are measured to establish or rule out the diagnosis of endogenous hypercortisolism. Mind that urinary-free cortisol values are inconsistently elevated in patients with obesity (94), though some studies have shown a relationship between BMI and waist circumference and UFC (102).
R.3.8. In all patients with confirmed hypercortisolism, an ACTH should be measured and further imaging should be performed to find the cause/source of the hypercortisolism.
Reasoning:
ACTH measurements, which are not altered by obesity (103), should be performed to investigate the cause of hypercortisolism. These further measurements and examinations will help to establish the exact causes of hypercortisolism and guide the therapeutic approach. In cases of ACTH-independent hypercortisolism the appropriate imaging methods (non-contrast CT as primary choice) are necessary to distinguish between benign or potentially malignant type of adrenal mass
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(104). When normal or high ACTH values are detected in patients with confirmed hypercortisolism pituitary MR and in some cases inferior petrosal sinus sampling should be performed to differentiate Cushing’s disease of pituitary vs ectopic origin (78).
R.3.9. Treatment of proven endogenous hypercorti-solism is not normalizing BMI in most cases. Reasoning:
In case of confirmed hypercortisolism, treatment of hypercortisolism has the highest priority. Although endogenous hypercortisolism contributes to weight gain, its treatment (surgical or conservative) does not lead to normalization of BMI in the majority of patients (105, 106). These findings suggest that endogenous hypercortisolism is in most of the patients a contributing factor rather than a sole cause of obesity.
5.4. Testing for hypogonadism in males
R.4.1. We recommend that biochemical testing for hypogonadism is not routinely applied in male obese patients; we do recommend investigating key clinical symptoms/signs of hypogonadism (++00).
Reasoning:
Male obesity-secondary hypogonadism (low plasma testosterone concentrations) has been reported in up to 45% of patients with moderate-to-severe obesity (107); in our review, we found a pooled prevalence of hypogonadism based on free testosterone measurements of 32.7% (95% CI: 23.1–43.0) (16). Moreover, obesity impairs sperm concentration, motility and morphology (108). Patients with obesity and associated comorbidities such as metabolic syndrome or type 2 diabetes exhibit a higher prevalence of hypogonadism (109). In fact, 75% of patients with class III obesity waiting for bariatric surgery have hypogonadism on the basis of a testosterone value lower than 12.1 nM/L (110). Accordingly, severe obesity is listed as a cause of functional secondary hypogonadism (111). Other terms such as late-onset hypogonadism and dysmetabolic hypogonadotrophic hypogonadism may also apply to this condition reflecting the participation of several metabolic factors such as obesity, visceral fat excess, insulin resistance, inflammation, oxidative stress and type 2 diabetes in its pathophysiology (107, 108, 111, 112, 113, 114, 115). There are multilateral relationships between obesity, hypogonadism, type 2 diabetes and metabolic
syndrome. Thus, obesity-associated comorbidities are commonly accompanied by low testosterone values and, on the other hand, low testosterone plasma values are associated with obesity, metabolic syndrome and type 2 diabetes (116). The increase in aromatase activity in adipose tissue, responsible for converting testosterone into oestradiol, may also contribute to inhibit LH secretion and reduce testosterone (117), as well as oestradiol blood levels (109). A dysregulation of the hypothalamic–pituitary–adrenal axis inducing functional hypercortisolism in obesity may also play a role in gonadotrophin inhibition and, consequently, reduced testosterone levels (94). As for the general population (111), a routine hormonal screening for male hypogonadism is not recommended in patients with obesity, and testing should be considered when clinical features create the need for investigating hypogonadism (Table 5). Therefore, we recommend investigating routinely key clinical symptoms/signs of hypogonadism in all men with obesity, including proper testicular size assessment. In line, we suggest that obese patients with metabolic syndrome and/or insulin resistance and/or type 2 diabetes are tested for the presence of hypogonadism especially if the clinical picture is suspicious of hypogonadism (113, 118).
R.4.2. In male patients with obesity with clinical features of hypogonadism we suggest measuring total and free testosterone (or calculated), SHBG, FSH and LH.
Reasoning:
Once clinical suspicion has been established, total testosterone plasma concentrations represent the initial Table 5 Clinical symptoms/signs of male hypogonadism.
Erectile dysfunction*
Weakness of morning erections* Reduced sexual desire*
Reduction in lean body mass Muscle weakness*
Gynoid fat distribution* Hot flushes*
Osteoporosis* Infertility*
Changes in mood, fatigue* Cognitive impairment Sleep disturbances*
Decreased androgenic body hair
Gynaecomastia and reduced testicular volume
Other symptoms/signs of anterior pituitary dysfunction
*Indicate some non-specific symptoms that are relevant for male obesity-secondary hypogonadism diagnosis.
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tool for investigating hypogonadism (111). Since there is a circadian rhythm of testosterone secretion, the sample should be taken in the morning between 0700 and 1100 h or within 3 h after waking-up in case of shift workers (119). On the other hand, daily circadian rhythm and pulsatile LH and testosterone pattern tend to flatten with increasing age (120). Low testosterone concentrations should be confirmed by taking morning samples in two separate days in fasting state, since food intake suppresses testosterone levels (111, 119). It is recommended to measure free testosterone levels when total testosterone is found to be near the lower limit of the normal range (111). In those situations, SHBG and free testosterone concentrations determine biochemical basis for the diagnosis of male hypogonadism (121, 122).
However, since the gold standard procedure to measure free testosterone (equilibrium dialysis) is not widely available, it may be preferable to calculate bioavailable testosterone by using testosterone, sex hormone-binding globulin (SHBG) and albumin concentrations (111, 123). This suggestion applies especially to obesity, since body fat excess and insulin resistance are commonly associated with low SHBG circulating values (111, 116), complicating the interpretation of testosterone concentrations. In general, a combination of low testosterone levels with clinical features of hypogonadism such as decreased sexual thoughts, erectile dysfunction and reduced morning erections is required for a formal male obesity-secondary hypogonadism diagnosis (117).
Once low testosterone concentrations have been demonstrated, FSH and LH measurements are useful to distinguish between primary and secondary hypogonadism (111). Male obesity-secondary hypogonadism is associated with low plasma gonadotrophin concentrations, and in some cases with predominance of FSH over LH (107), in contrast with primary hypogonadism, where gonadotrophins are elevated. Once hypogonadotrophic hypogonadism has been diagnosed, other causes of secondary hypogonadism should be excluded before attributing the hormonal disorder to obesity; especially hyperprolactinaemia, leptin signaling abnormalities, syndromic or hypothalamic obesity are frequently associated with hypogonadotrophic hypogonadism (111). When secondary hypogonadism has been confirmed biochemically, morphological exploration of the hypothalamic–pituitary region by MRI may also be needed in selected patients (111). If imaging exploration is negative leptin assessment and genetic evaluation have to be considered.
R.4.3. In obesity we suggest applying age specific reference ranges for testosterone (+000).
Reasoning:
Male testosterone levels decrease with age, though recent reports suggest that the magnitude of testosterone reduction seems to be lower than previously thought (124, 125). Nevertheless, these studies are based on single morning samples, disregarding pulsatile, diurnal and circannual testosterone rhythms. Although obesity is associated with an increased prevalence of hypogonadism, no adjustments for BMI are used to confirm the biochemical diagnosis of hypogonadism (107). Moreover, testosterone measurements are affected by chronic diseases, medications, genetics, lifestyle, and intra-individual variations (126). All these aspects should be considered when interpreting a testosterone result.
Testosterone results also depend on the assay technique used. Most available testosterone assays are immunoassays (RIA, enzyme immunoassay or fluoroimmunoassay), which are rapid, simple and inexpensive. Moreover, most reference ranges have been established using immunoassays. However, their accuracy is lower than that obtained by mass spectrometry, which is more expensive and requires regular calibration. Nevertheless, liquid chromatography tandem mass spectrometry (LC-MS) has become progressively adopted showing better precision (118, 125, 126). Variability between immunoassays and LC-MS ranges from −14 to +19%, (127). Preparation and handling of the sample as well as calibration also have an impact on variability (126).
Equilibrium dialysis represents the gold standard method to measure free testosterone but is expensive and technically challenging. For practical reasons, most guidelines recommend direct measurements or calculation of free testosterone by a formula. Correlation with measurements performed with equilibrium dialysis is good, but results depend on dissociation constants for binding of SHBG and albumin and on the accuracy of assays used (see for review (126)).
Regarding normal reference ranges for testosterone, the Endocrine Society proposes 9.2−31.8 nmol/L in healthy men aged 19−39 years (125), whereas the Endocrine Society of Australia considers a range of 10.4-30.1 nmol/L for men aged 21-35 years and 6.4-25.7 nmol/L for men aged 70-89 years measured by mass-spectrometry without specific reference to obese people (128). The European Male Aging Study has suggested a cut-off value of total testosterone of 11 nmol/L (3.2 ng/mL) to define hypogonadism associated to the presence of three sexual symptoms (118), which
